A Novel Cascade Reaction of Aryl Aldoxime with Dimedone under Microwave Irradiation: The Synthesis of N-Hydroxylacridine

Article abstract of DOI:10.1055/s-2003-44981

A novel sequential addition, elimination and cyclization reactions took place when aldoxime and dimedone in glycol was subjected to microwave irradiation and a new type of N-hydroxylacridinedione derivatives was obtained in excellent yields (80-95%) within a short reaction time (4-8 min).

Full text of DOI:10.1055/s-2003-44981

LETTER
255
A Novel Cascade Reaction of Aryl Aldoxime with Dimedone Under Microwave
Irradiation: The Synthesis of N-Hydroxylacridine
T
he Synthesis
h
of
N
-Hydrox
u
ylacridine jiang Tu,*a Chunbao Miao,a Yuan Gao,b Fang Fang,a Qiya Zhuang,a Youjian Feng,a Daqing Shia
a
Department of Chemistry, Xuzhou Normal University, Key Laboratory of Biotechnology on Medical Plant, Xuzhou; Jiangsu, 221009,
P. R. China
Fax +86(516)3403164; E-mail: laotu2001@263.net
b
Department of Chemistry, Shenzhen University, Shenzhen; Guangdong, 518060, P. R. China
Received 28 August 2003
ever, the introduction of a hydroxyl on the nitrogen atom
of acridine has not been reported.
Abstract: A novel sequential addition, elimination and cyclization
reactions took place when aldoxime and dimedone in glycol was
subjected to microwave irradiation and a new type of N-hydroxyl-
acridinedione derivatives was obtained in excellent yields (80–
95%) within a short reaction time (4–8 min).
Oximes are important intermediates in organic synthesis
such as in 1,3-dipolar cycloadditions,7 and can be applied
in the preparation of heterocycles.8 It was recently found
that these reactions can be accelerated by microwave irra-
diation (MW).9 Since microwave heating was first used
for organic synthesis by Gedye10 in 1986, the MW assist-
ed organic synthesis has been a topic of continuing inter-
est.11 The relative low cost of modern domestic
microwave ovens makes them readily available to aca-
demic and industrial chemists.12 In this paper, we report a
novel cascade reaction of oximes with dimedone under
microwave irradiation that leads to the synthesis of a new
type of heterocyclic compounds, the N-hydroxylacridine
derivatives (Scheme 1).
Key words: aryl aldoxime, dimedone, N-hydroxylacridine, micro-
wave
1,4-Dihydropyridines (1,4-DHPs) are well-known com-
pounds because of their pharmacological profile as calci-
um channel modulators.1 The chemical modifications of
the DHP ring such as the introduction of different substit-
uents or heteroatoms2 have allowed expansion of the re-
search to structure-activity relationship to afford new
insight into the molecular interactions at the receptor lev-
el. In fact, it is well-established that slight structural mod-
ification on the DHP ring may bring significant change in
pharmacological activities.3 Acridine belongs to a special
class of compounds not only because of their interesting
chemical and physical properties but also due to their im-
mense utility in pharmaceutical and dye industry. With an
1,4-DHPs parent nucleus, acridines are well known ather-
apeutic agents.4 The discovery of acridines as antimalarial
and antitumor agents has attracted the attention of organic
chemists and led to intensive interest in the synthesis of
several drugs based on acridine.5 The introduction of aryl
on the nitrogen of acridine causes laser activity.6 How-
As a part of a research program directed towards the de-
sign and synthesis of lead compounds for potentially in-
teresting drugs, aldoxime was taken into consideration as
a possible starting point to obtain new substances with
pharmacological activity. In our recent efforts aiming at
synthesizing compound 5, we treated 1 and 2 in glycol un-
der microwave irradiation. However, instead of the de-
sired compound 5, a new compound 9-substituded-N-
hydroxyl-1,2,3,4,5,6,7,8,9,10-decahydro-acridine-1,8-di-
one (4) was obtained.13
O
R
NH
R1
R
O
O
O
O
R1
R1
R1
5
NH4OAC
+
R
CH NOH
R1
R1
II
R
O
N
H
O
R1
O
I
R1
R1
R1
R1
R1
3
1
2
N
OH
4
Scheme 1
SYNLETT 2004, No. 2, pp 0255–0258
0
2.
0
2.
2
0
0
4
Advanced online publication: 08.12.2003
DOI: 10.1055/s-2003-44981; Art ID: U17003ST
© Georg Thieme Verlag Stuttgart · New York

256
S. Tu et al.
LETTER
R
NHOH
..
OH
O
O
H
R1
O
O
R C NOH +
H
+
RCH
NH2OH
R1
R1
O
R1
R1
R1
R1
R1
1
7
2
6
O
O
..
HOHN
O
O
N
R
O
O
R1
R1
R
R1
R1
R1
R1
R1
R1
R1
R1
O
R1
..
NH
OH
+
RCH
O
R1
O
O
OH
O
10
9
7
8
O
R
O
O
R
O
-H2O
R1
R1
R1
R1
R1
R1
R1
N
OH
N
H
R1
OH
4
11
Scheme 2
This reaction may occur via the (addition, elimination, ad- firmed by X-ray diffraction study (Figure 1). In this case,
dition, cyclization) mechanism shown in Scheme 1. The a similar mechanism is involved. The nucleophilicity of
Michael addition between aldoxime and 1,3-dicarbonyls ammonia (from ammonium acetate) was stronger than
gave the intermediate 6 which on elimination of NH2OH NH2OH, which led to the formation of 3. When ketoximes
gave 2-aryllidene-1,3-cyclohexanedione (7). Michael ad- were used in place of aldeoximes, these reactions could
dition between 7 and 8 (obtained from dimedone 2 and not take place.
NH2OH) then furnished the intermediate 9, which isomer-
ized to 10. Intramolecular cyclodehydration of 10 gave 4
(Scheme 2). The structure of compound 4a (containing a
In summary, we have disclosed a novel reaction between
aldoxime and dimedone and realized the introduction of
the hydroxyl to the nitrogen atom of acridine derivatives,
which provided a rapid, efficient and environmentally
water molecule, Figure 2) was confirmed by an X-ray
crystallographic analysis.14
friendly method for the synthesis of N-hydroxyl acridine
When ammonium acetate was added to this reaction sys- derivatives. This method not only could be applied to
tem under the same conditions, acridine derivatives 3 aromatic aldoxime but also to heterocyclic and aliphatic
were obtained (Table 1). The structure of 3g was also con- aldoxime. These N-hydroxylacridinedione derivatives are
expected to exhibit interesting biological properties,
which are currently under investigation.
Figure 1 The structure of 3g
Figure 2 The structure of 4a
Synlett 2004, No. 2, 255–258 © Thieme Stuttgart · New York

LETTER
The Synthesis of N-Hydroxylacridine
257
Table 1 Synthesis of Acridine Derivatives 3 and 4
Entry
3a
3b
3c
3d
3e
3f
Oxime
R1
Time (min)
Yield (%)
Mp (°C) (literature)
284–285 (283–285)15,16
221–223 (221–223)16
221–223 (221–223)16
264–266 (264–266)15,16
258–260
3-NO2C6H4CH=NOH
2-Cl C6H4CH=NOH
4-ClC6H4CH=NOH
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
6a (85)b
80a (76)b
86a (85)b
92a (88)b
88
5a (90)b
5a (70)b
4-(CH3)2NC6H4CH=NOH
3,4-(CH3O)2C6H3CH=NOH
3,4-(OCH2O)C6H3CH=NOH
4-CH3 °C6H4CH=NOH
1,4-C6H4(CH=NOH)2
2-furyl-CH=NOH
6
5
5
5
8
5
4
4
4
5
5
6
5
4
6
5
5
7
6
5
6
4
7
5
4
4
5
8
8
8
84
80
324–326
3g
3h
3i
88
269–270 (269–270)15
>300
90
85
>300
3j
CH3CH2CH=NOH
89
282–283
3k
3l
CH3CH2CH2CH=NOH
CH3CH2CH2CH2CH=NOH
(CH2)3(CH=NOH)2
91
286–287
92
227–228
3m
4a
4b
4c
4d
4e
4f
95
>300
4-FC6H4CH=NOH
90
233–234
2-ClC6H4CH=NOH
88
222–223
4-ClC6H4CH=NOH
92
256–257
3,4-(OCH2O)C6H3CH=NOH
4-CH3OC6H4CH=NOH
3-NO2C6H4CH=NOH
4-NO2C6H4CH=NOH
4-(CH3)2NC6H4CH=NOH
1,4-C6H4(CH=NOH)2
2-furyl-CH=NOH
93
248–249
90
146–147
92
136–137
4g
4h
4i
95
134–135
88
159–160
92
>300
4j
83
196–197
4k
4l
4-CH3OC6H4CH=NOH
4-ClC6H4CH=NOH
85
>300
H
86
>300
4m
4 n
4o
4p
4q
4r
4s
2-OH-4-OCH3C6H3CH=NOH
CH3CH2CH=NOH
H
88
237–238
CH3
CH3
CH3
CH3
CH3
CH3
CH3
81
204–205
CH3CH2CH2CH=NOH
CH3CH2CH2CH2CH=NOH
(CH2)3(CH=NOH)2
85
152–153
86
115–116
89
218–220
C6H5C(CH3)=NOH
0
–
4-ClC6H4C(CH3)=NOH
(CH3)2C=NOH
0
–
4t
0
–
a Method A in glycol under the irradition of MW.
b Method A in glycol at 100 °C.
Synlett 2004, No. 2, 255–258 © Thieme Stuttgart · New York

258
S. Tu et al.
LETTER
cm–1. 1H NMR (DMSO-d6): d = 0.92 (s, 6 H, 2 × CH3), 1.02
(s, 6 H, 2 × CH3), 2.03–2.41 (m, 8 H, 4 × CH2), 4.98 (s, 1 H,
CH), 5.81 (d, 1 H, J = 3.00 Hz, furan H), 6.21 (dd, 1 H,
J = 3.08 Hz, furan H), 7.35 (d, 1 H, J = 0.90 Hz, furan H),
9.36 (s, 1 H, NH). Compound 3j: IR (KBr): 3280, 3209,
3068, 2959, 2930, 2871, 2721, 1645, 1600, 1488, 1381,
1309, 1273, 1244, 1225, 1188, 1169, 1143, 1121, 1065,
1006, 885, 870, 775, 733, 693, 648, 618, 572, 560 cm–1. 1H
NMR (DMSO-d6): d = 0.63 (t, 3 H, J = 7.56 Hz, CH3), 1.02
(s, 12 H, 4 ´ CH3), 1.24–1.26 (m, 2 H, CH2), 2.02–2.27 (m, 8
H, 4 × CH2), 3.80 (t, 1 H, J = 5.25 Hz, CH), 8.99 (s, 1 H,
NH). Compound 4c: IR (KBr): 3300, 2961, 2878, 2674,
1603, 1568, 1490, 1409, 1371, 1323, 1272, 1225, 1141,
1023, 902, 848, 565, 523 cm–1. 1H NMR (DMSO-d6): d =
0.87 (s, 6 H, 2 × CH3), 1.04 (s, 6 H, 2 × CH3), 2.02–2.68 (m,
8 H, 4 × CH2), 4.93 (s, 1 H, CH), 7.14 (d, 2 H, J = 6.3 Hz, Ar
H), 7.25 (d, 2 H, J = 6.3 Hz, Ar H), 10.79 (s, 1 H, OH).
Compound 4i: IR (KBr): 3225, 2954, 2871, 1667, 1660,
1504, 1462, 1504, 1462, 1369, 1229, 1154, 1010, 808, 661,
582 cm–1. 1H NMR (DMSO-d6): d = 0.82 (s, 12 H, 4 ´ CH3),
1.02 (s, 12 H, 4 ´ CH3), 2.00–2.65 (m, 16 H, 8 ´ CH2), 4.47
(s, 2 H, 2 ´ CH), 6.95 (s, 4 H, Ar H), 10.73 (s, 2 H, 2 ´ OH).
Compound 4j: IR (KBr): 3308, 2958, 2930, 2867, 2728,
1605, 1562, 1501, 1469, 1359, 1324, 1262, 1220, 1142,
1072, 1007, 1072, 979, 951, 921, 884, 781, 727, 683, 616,
600, 566 cm–1. 1H NMR (DMSO-d6): d = 0.94 (s, 6 H,
2 × CH3), 1.05 (s, 6 H, 2 × CH3), 2.07–2.61 (m, 8 H,
4 × CH2), 5.12 (s, 1 H, CH), 5.84 (d, 1 H, J = 3.3 Hz, furan
H), 6.25 (dd, 1 H, J = 3.0 Hz, furan H), 7.35 (d, 1 H, J = 0.81
Hz, furan H), 10.85 (s, 1 H, OH). Compound 4k: IR (KBr):
3278, 3186, 3052, 2945, 1644, 1603, 1490, 1362, 1229,
1173, 1127, 1034 cm–1. 1H NMR (DMSO-d6): d = 1.76–1.95
(m, 4 H, CH2), 2.19–2.22 (m, 4 H, =C–CH2–), 2.29–2.48 (m,
4 H, –CO–CH2–), 3.67 (s, 3 H, CH3), 4.85 (s, 1 H, CH), 6.72
(d, 2 H, J = 8.4Hz, Ar H), 7.05 (d, 2 H, J = 8.4 Hz, Ar H),
9.37 (s, 1 H, OH). Compound 4n: IR (KBr): 3298, 2962,
2958, 2966, 2657, 1627, 1552, 1464, 1389, 1298, 1233,
1172, 1144, 1074, 1002, 934, 905, 887, 778, 740, 685, 612,3,
567 cm–1. 1H NMR (DMSO-d6): d = 0.66 (t, 3 H, J = 7.50
Hz, CH3,), 1.02 (s, 6 H, 2 ´ CH3), 1.05 (s, 6 H, 2 ´ CH3),
1.16–1.20 (m, 2 H, CH2), 2.06–2.63 (m, 8 H, 4 × CH2), 3.85
(t, 1 H, J = 5.25 Hz, CH), 10.60 (s, 1 H, OH).
Acknowledgment
We thank for the National Natural Science Foundation of China
(No. 20372057), the Nature Science Foundation of the Jiangsu
Province (No. BK2001142) and the Nature Science Foundation of
Jiangsu Education Department (No. 01KJB150008) and the Key
Laboratory of Chemical Engineering & Technology of the Jiangsu
Province Open Foundation (No. KJS02060) for financial support.
References
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(14) The sing-crystal growth was carried out in EtOH at r.t. X-ray
crystallographic analysis was performed with a Siemens
SMART CCD and a Siemens P4 diffractometer (graphite
monochromator, MoKa radiation l = 0.71073 Å). The
crystal crystallizes with one water molecule. Crystal data for
3g: C24H29NO3, yellow, crystal dimension
0.80 × 0.80 × 0.30 mm, orthorhombic, space group Pca2 (1),
a = 1.41862 (3), b = 1.51896 (3), c = 2.07611 (1) Å,
a = g = b = 90°, V = 4.47366(13) Å3, Mr = 379.48, Z = 8,
Dc = 1.27 g/cm3, l = 0.071073 Å, m (MoKa) = 0.074 mm–1,
F(000) = 1632, S = 1.144, R1 = 0.0652, wR2 = 0.1510.
Crystal data for 4a: C23H28ClFNO4, yellow, crystal
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(13) The General Procedure is Represented Below: The
mixture of substituted aryl aldeoxime (2 mmol) and
dimedone (4 mmol) in glycol (5 mL) was irradiated for 4–6
min. The reaction mixture was cooled to r.t. and poured into
50 mL of H2O, filtered to give the crude product, which was
further purified by recrystallization from 95% EtOH. All
products are characterized by IR and 1H NMR spectral data.
Typical spectral data: compound 3i: IR (KBr): 3285, 3069,
2957, 2867, 1624, 1605, 1483, 1396, 1364, 1251, 1170,
1141, 1069, 1012, 981, 922, 886, 816, 773, 728, 599, 567
dimension 0.58 × 0.58 × 0.40 mm, monoclinic, space group
P2(1)/c, a = 12.638(2), b = 14.039 (3), c = 11.102 (2) Å,
= 94.60 (1)°, V = 2140.2 (6) Å3, Mr = 401.46, Z = 4,
Dc = 1.246 g/cm3, l = 0.71073 Å, m (MoKa) = 0.09 mm–1,
F(000) = 856, S = 0.906, R1 = 0.0398, wR2 = 0.0932.
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Synlett 2004, No. 2, 255–258 © Thieme Stuttgart · New York